Abstract The goal of this administrative supplement is to expand the funded research award to develop a specific focus on Alzheimer's disease (AD) by introducing a model of familial AD, apolipoprotein E4 (APOE4), and investigating disrupted compartmental redox status, alterations in the thiol redox proteome and how these mechanisms impact central carbon metabolism basally and after exposure to the fungicide maneb (MB). AD is the most common neurodegenerative disease globally, and the number of cases is expected to increase by 300% over the next 40 years. Less than half of all AD cases can be attributed to the handful of genes; however, exposures to toxicants like metals, solvents, and pesticides have been reported to be potential environmental contributors to the disease. Due to this environmental involvement it is extremely important to understand the mechanistic consequences of exposures and how these specific mechanisms may play a role in the etiology of AD. Furthermore, the APOE4 allele has a strong effect on AD susceptibility and represents the strongest genetic risk factor for AD to date. Interestingly, not all APOE4 carriers will develop AD, suggesting that environmental factors can impact the development of pathology and modulate clinical manifestation; therefore, it is critically important to investigate the influence that environmental toxicants have in this genetic condition. The currently funded R01 research (R01 ES027593) aims to elucidate the thiol redox mechanisms that increase xenobiotic toxicity, alter neurogenesis and enhance neurodegeneration. The chosen model for this research is Down syndrome (DS), which represents a significant population that remains understudied. DS is complex, variable, and phenotypes result from interactions between altered gene expression, due to trisomy 21, and environmental insults. Integration of the APOE4 model of familial AD is a logical extension of the proposed work due to the fact that both APOE4 mutants and DS individuals share many comorbidities (obesity, diabetes) and both develop AD pathology and dementia far earlier than other forms of AD. Based upon our preliminary observations in DS cells and observations in the literature, we hypothesize that cells from APOE4 mutants and DS individuals display altered redox homeostasis, which contributes to early onset AD due to impaired proteostasis and central carbon metabolism. Because proteostasis dysfunction and oxidative stress are fundamental mechanisms of neurodegeneration, this proposal will investigate the role of redox signaling and control in APOE4 mutant fibroblasts and neuroprogenitor cells (NPC), how these redox changes alter central carbon metabolism, and will identify mechanistic similarities in two models of early-onset AD. Therefore, the methods outlined here will lead to valuable observations pertaining to thiol redox proteomic and metabolic alterations that occur in early-onset AD. Lastly, this proposal, with explicit goals to better understand the biology of neurodegeneration, capitalizes on my previously funded research, my expertise in oxidative stress and mechanistic toxicology, and the established core facilities present at the University of Colorado.